Diphenyl derivatives



' Patented Mar. 16, 1937 UNITED STATES PATENT; OFF-ICE Zurich,Switzerland, assilnors to E. B. Squibb & Sons, New York, N. 12, acorporation of New York No Drawln. Application October SerialNo.692,124

'lClaims.

I This invention relates to, and has tor-its oblect the provision of,certain new compounds, usefulas intermediates in the'preparation oibactericides.

Compounds 01 this invention have the general formula v v 4 wherein xrepresents an allryl, an soy], or anamino or substituted amino group andY represents an alkyl when x is an amino group but otherwise representshydrogen or an alkyl.

Exmus Z-hudrosv i-n-amyl diphemll g. 2-hydro1w'5-n-valeryldiphenyl. 60at amalgamated zinc, 200 cc. hydrochloric acid wand 40 cc. alcohol aremixed and refluxed with vigorous agitation for 10-12 hours; aftercooling, the oily product is extracted from the aqueous reactionmixturetby means of ether or some-other suitable solvent; the ethersplution is thoroughly washed with water and dried with anhydrous sodiumsulfate; the ether is removed by'distillation; and the residue beingdistilled under reduced pressure, the desired compound is collected at181-183l6 mm. e

80 Similar reduction oi the correspondins acyl hydroxy diphenyls bymeans 01 amalgamated zinc and hydrochloric acid yields Z-hydrorw3-n-butyl diphenyl, boiling at 167/4mr n.: Z-hydroxy 5-nbutyl diphenyl,boiling at 173-17576 mm.; 2-

36 hydroxy 3-n-amyl diphenyl, boiling at 168-1'li'l5 mm. The compoundsZ-methoxy S-ethyl d1.- phenyl, boiling at 163-168/7 mm.; Z-methoxylS-n-propyl diphenyl, boiling at 1'11-1'12'l9 mm.;"

2-methoxy 5-n-amyl diphenyl, boiling at 1'18- 40 raw/5 mm.; may beprepared by boiling to-l sether under a reflux, with vigorous agitation.one part 0! the corresponding Z-methoxy B-acyl diphenyl. three partsamalgamated zinc. three parts concentrated hydrochloric acid, and sixparts water; extracting from the acid reaction mixture the methoxy alkyldiphenyl so.

formed, with a suitable solvent such as etheror. benzene; washing treeoi zinc salts, drying by means of calcium chloride; removing the solventby distillation: and distilling the residue in vacuo.

Z-hydrocy J-n-oolerwi diphenul, Z-hydr'ow 5-1:-

4 voters! diphenvl r sac maluminum chloride-is added in portions to 50.8I. fl-phenyl-phenyl nera in g. dry nitrobenzene;

mixed and arms. 1

the mixture v1e heated at until the evolution 01' hydrogen chlorideceases'and is then cooled;

the red glassy product is treated with cold dilute hydrochloric acid;the mixture is warmed on the water-bath until completely decomposed; the

precipitated mixture or the desired compounds is thoroughly washed withhydrochloric acid to remove aluminum saltsand then with. water, and isdissolved in ether or some other suitable solvent;

:the solution is dried with anhydrous sodium sullate; the residue isdistilled under reduced pressure the portion boiling above 210/'l mm. iscollected, allowed to solidify by cooling, shaken with several 250 cc.portions oi'petroleum ether boiling at 60-80; the undissolved yellowsolid residue, 2-hydroxy5-n-valeryl diphenyl, on recrystallization froma mixture 01 ether and petroleum ether, forms a white microcrystallinepowder melting at 104; the petroleum ether washings are combined and thepetroleum ether removed by distillation; and distillation oi! theresidue under reduced pressure yields 2-hydroxy 3-'n-. valeryl dipherrvlas a faintly yellow oil boiling at 200-210/5 mm. e

- Z-hudrorw 3-n-b1rtvrwl diphenyl, Z-hudrow 5-1:-

butunll diphem l I 24 g. z-phenyl-phenyl n-butyrate is dissolved 16 g.anhydrous aluminum' chloride is added; the reaction vessel, protectedfrom atmospheric moisture, is allowed to stand for two days; suflicientdilute hydrochloric acid is added to dissolve the aluminum salt; thenitrobenzene .is removed by steam distillation; after cooling. theaqueousportion oi the mass is decanted from the thick oily precipitateoi the desired compounds. which is dissolved in ether: the solution iswashed thoroushly with dilute hydrochloric acid and water and dried-withanhydrous sodium sulfate; the solvent is removed; the

residue is distilled under reduced pressure; and

the portion boiling at 190-220/6 .mm. is collected; and the desiredcompounds are separated as in the preceding example, utilization beingmade 0! the fact that the S-n-butyryl compound is" much more readilysoluble in petroleum ether than the fi-n-but'yryl compound. p

. zl r -mmvl wh n! 78 s. 2-methoxy diphenyl is dissolved in 150 cc. 'drycarbon disulflde;' 112 3. aluminum chloride is cautiously added; while88 s. propionic anhydride is added durinshali an hour, and ior an hourthereaiter. the is :ently'revigorous of hychloride taking place;thecarbon flde is removed by distillation: the hot residue is intocracked ice and hydrochloric acid to-remove the aluminum; the ketone soliberated is extracted with ether, and is washed with water, ustic sodasolution. and again with water to more the aluminum salts; the etherealsolution isdried withcalciumchloride': theetherisdis tilled oil; theresidue is allowed to crystallize; IO and recrystallisation frompetroleum ether yields ing at 08-04.

I-Mhocy S-n-valeryl diphmyl A liquid distilling at 202-304'/4.mm. is prepared by a process exactly analogous to that of the preceding example. v

8-bedroom i-dcetylamiho diphenyl 12 g. Z-hydroxy S-amino diphenyl issuspended 80 cc. water: 12 cc.acetic anhydride is added a thin stream,with vigorous stirring; the

and crystallised purplish tarry matter is iiltes'bd oil and dissolved in30% alcohol; the

. 2.1 g.adium (0% excess) isdissolvedin65 cc. absolute alcohol: 18 g.Z-hydron -acetylaminodiphenylisadded; themixtureiscooiedf ethyl bromide(a excess) is added:

reactioniiaskisstoppered andallowed'to 4 .alcohoLanddigestedonasteam-hath with 8 g. activated carbon until colcrises on filtering;addition oi two volumes orwatartothehotflltratecausesthedesiredcomdlpoundbmteoutinshiningwhiteplateletameltingatits (uncorrected).

vllcroualyahahen: 11 lllodiumaeetateinildccwaterialddcdfthemtahhrokenupanddl-olvedinalcohontheaolntionisdigestedwithactivatedcarheateriourhoursatfm andilltared; otwateroameathe Americana-manure. ieopropylbora'te. 15 I. alumina chloride. uandmcadrynitrobenaeneisheatadforthrecnitrobensene,

deooloriaed with carbon; and, the illhours on the. steam-bath and thenpoured into dilute hydrochloric acid; the nitrobensene is removed bysteam distillation: the distillation res,- idue is; extracted withether; the extract is washed with dilute hydrochloric acid. and waterand dried; and fractional distillationyields the desired compound,boiling at 124-42872 mm.

z-methozu S-isoproppl diphcnrl A mixture or 33 g. 2-methoxy diphenvl,186 g. 12.8 g. tri-isop opyl borate, and 12 g. anhydrous aluminumchloride is allowed to stand over night, heated on the steam-hath iortwo hours, and then poured into 500 cc. 01- dilute hydrochloric acid;the nitrobennene is re- .moved by steamdistillation; the residue isextracted with ether; the extract is washed successively with dilutesodium hydroxide, dilute hydrochloric acid. and water, dried withcalcium chloride, and iractionally distilled; removal of ether from theresidue yields the desired pound. boiling at 140-145l2 mm.

z-ethosy s-carbamido diphenul 1.5 g. Z-ethoxy 5-amino diphenyl isdissolved in cc. hot water; after cooling. thesuspensionoi'crystakistreated withiigsolidpotassium cyanate and 3 cc. acetic acid,with continuous stirring; an additional 3 go! potassium cyanate'andaccaceticacidareaddedandthemixture' allowed to stand over night; thecrystalline precipitate, on being filtered and recrystallised fromalcohol or benzene. yields the desired co as a crystalline solid meltingat 178-177.

.l-hgdroxu d-n-propul diphenvl 8 g. S-methoxy B-n-propyl diphenyl isboiled driodic acid and cc. glacial acetic acid; themixtureisdilutedwithiivolumesoi water-and neutralized with sodiumcarbonate; the oil is extracted with ether; the extract is shaken re--peatedly with dilute sodium hydroxide solution; the alkaline extract isacidified with hydrochloric acid; and the desired compound precipitatesas anoilthatsooncrystalliaesandonrecrystalliaation from a mixture ofbenzene and petroleum ether. melts at -141".

.i-mcthozu swim am:

85 g. 8-methoxy diphenyi is dissolved in 80cc. carbon disuliide; 5'! g.anhydrous aluminum chloride is added; the mixture. while stirred. isgently refluxed on the steam-hath: 20- g. propicnic anhydride is addeddropwisedm'ing halt anhounstirringandrcfluxingarecontinued (aboutiorty-iive. minutes) until evolution ot hydrogen chloride ceases; thecar-hon disulilde is distilled 01!; the residue is decomposed bytreatment with ice and hydrochloric acid and then for seven hours with75 cc. concentrated-hyi 1 warming onthe steam-bath: the semi-solidproduct is extracted with etha': the extract is washed with 5% sodiumhydroxide and water and dried with calcium chloride: after removal oithe ether, the residue distills at -10073 mm.': on

cooling, the distillate yieldsthe desired compound. which. onrecrystallization from petroleum ether. meltsat12'. .i-methoxu 8mm: my:

26 g. S-methon G-propionyl diphenyl is re and 500 cc. 1:1 hydrochloricacid; extraction.

washing. anddistiliationasin th'egroupoiex-,

amples .ilrst above given, yields the desired pound, boiling at153-17i)/3 mm.

3-hudrorv l-n-propyl diphenul commeltingfat 56-665".

:i-hydrocu 4-propiimyl diphenyl mixture is heated to 160*. and keptthereat until evolution oi hydrogen chloride ceases; after cooling, themass is powdered, and decomposed by warming on the steam-bath withdilute hydrochloric acid; the precipitate isfiltered off, washed withwater, dried, andextracted thrice with boiling petroleum ether: oncooling, the extracts deposit'the desired compound, which onpurlflcalimitatlve o! the invention, which may be variously otherwiseembodied-as with respect to particular compounds and methods oipreparing them-within the scope of the appended claims.

We claim f 1.- B-hydroxy 5-n-butyl diphenyl. 2. 2-hydro1w 5-n-valeryldiphmyl.

3. 2-ethoxy 5-acetylamino dlphenyl. 4. Compounds of the group consistingof loweralkyl. iower-aliphatic-acyl, lower-aiiphatic-aeylamino,benzalamino, and carbamido ihydroxyand I V v alkoxy diphenyls) aminoalkoxy diphenyls, 32 g. S-phenyl-phenyl propionate is treated with 19.5g. anhydrous aluminum chloride; the

such substituent other than h'ydroxy and alkoxy .being attached to acarbon or the hydroxylated or alko wlated benzene nucleus. I

5. lnwer-alkyl 1 hydroxy diphenyls. the substituents being attached tocarbons otthe same benzene nucleus.

6. Lowerealiphatic-acyl hydroxy diphenyls, the

-substituents being attached to carbons of the same benzene nucleus.

lower-aiiphatic-acyl-amino alkoxy di- 7 ph'enyls, the subatituents beingattached to car- 7. bons of the same benzene nucleus.

WALTER a. SIDNEY n HARRIS. some m r blso l Al M E R 2,073,683.Walter 0.Christin/risen Glen Ridge, N. J. Sid E. Harris L b k I N Y., and JohnLee, Zurich, Switzerland. fi I PHENYL Dinar-2%;

Plan dated" March 16, 1937. the assignee, E. R. Squibb d: Sons. I Herebyenters this disclaimer to claims 5 and 6 Disclaimer filed September 17,1937,'by

of said Letters Patent and to such portions of claim 4 of said LettersPatent as are directed to lower-alk l h dr diphenyls,lower-aliphatic-acyl hydroxy diphenyls, and lower aliphatic-ai zyl isk gdiphenyls.

Gazette October 12, 1937.]

amples .ilrst above given, yields the desired pound, boiling at153-17i)/3 mm.

3-hudrorv l-n-propyl diphenul commeltingfat 56-665".

:i-hydrocu 4-propiimyl diphenyl mixture is heated to 160*. and keptthereat until evolution oi hydrogen chloride ceases; after cooling, themass is powdered, and decomposed by warming on the steam-bath withdilute hydrochloric acid; the precipitate isfiltered off, washed withwater, dried, andextracted thrice with boiling petroleum ether: oncooling, the extracts deposit'the desired compound, which onpurlflcalimitatlve o! the invention, which may be variously otherwiseembodied-as with respect to particular compounds and methods oipreparing them-within the scope of the appended claims.

We claim f 1.- B-hydroxy 5-n-butyl diphenyl. 2. 2-hydro1w 5-n-valeryldiphmyl.

3. 2-ethoxy 5-acetylamino dlphenyl. 4. Compounds of the group consistingof loweralkyl. iower-aliphatic-acyl, lower-aiiphatic-aeylamino,benzalamino, and carbamido ihydroxyand I V v alkoxy diphenyls) aminoalkoxy diphenyls, 32 g. S-phenyl-phenyl propionate is treated with 19.5g. anhydrous aluminum chloride; the

such substituent other than h'ydroxy and alkoxy .being attached to acarbon or the hydroxylated or alko wlated benzene nucleus. I

5. lnwer-alkyl 1 hydroxy diphenyls. the substituents being attached tocarbons otthe same benzene nucleus.

6. Lowerealiphatic-acyl hydroxy diphenyls, the

-substituents being attached to carbons of the same benzene nucleus.

lower-aiiphatic-acyl-amino alkoxy di- 7 ph'enyls, the subatituents beingattached to car- 7. bons of the same benzene nucleus.

WALTER a. SIDNEY n HARRIS. some m r blso l Al M E R 2,073,683.Walter 0.Christin/risen Glen Ridge, N. J. Sid E. Harris L b k I N Y., and JohnLee, Zurich, Switzerland. fi I PHENYL Dinar-2%;

Plan dated" March 16, 1937. the assignee, E. R. Squibb d: Sons. I Herebyenters this disclaimer to claims 5 and 6 Disclaimer filed September 17,1937,'by

of said Letters Patent and to such portions of claim 4 of said LettersPatent as are directed to lower-alk l h dr diphenyls,lower-aliphatic-acyl hydroxy diphenyls, and lower aliphatic-ai zyl isk gdiphenyls.

Gazette October 12, 1937.]

